This project's immediate research objective is to identify the potential role of mobile DNA elements known as retrotransposons in promoting aging-related genome instability, since retrotransposons are associated with chromosome rearrangements and mutations in human cells. This is part of a broader goal to establish an independent research program to address how retrotransposons influence genome stability and organization and how changes in genome stability relate to aging. The work will be conducted in a yeast model system. Similarities exist between yeast and humans in the genetic control and genetic consequences of aging, and yeast provides one of the only facile experimental systems to study endogenous retrotransposons. The mentored portion of the project will involve developing and obtaining preliminary data from experimental systems designed to test the influence of retrotransposons on the rate of chromosome rearrangements and mutations in aging yeast cells. Preliminary measurements of lifespans of mutant yeast strains with increased or decreased rates of mutations or chromosome rearrangements will also be made. During the independent phase, aging-related chromosome rearrangements will be analyzed at a sequence level. In addition, the influence of retrotransposition on mutation spectra during aging and the influence of compromising specific pathways crucial for genome maintenance on lifespan will be more fully explored. Interactions with the candidate's mentor and several other investigators in related research fields at the Wadsworth Center and access to core flow cytometry, microarray, and DNA sequencing facilities will provide necessary technical expertise to promote research independence. Technical expertise, guidance interpreting data, and discussions of current issues in aging research will be provided by a co-mentor at Roswell Park Cancer Institute. Attendance at courses, workshops, and conferences will also provide awareness of current issues in aging research. Acquisition of these skills and experiences will allow the establishment of an independent research program distinct from the research focus of the mentor for this project. RELEVANCE (See instructions): Damage and change to genetic information is associated with aging in many organisms, including yeast and humans. The goal of this project is to take advantage of the speed and efficiency of conducting research in yeast to identify a specific mechanism that contributes to genetic damage and changes during aging. This mechanism will then serve as a potential target for therapies to improve human health during aging.